Project Summary Colorectal cancer is the second leading cause of cancer-related death in the United States annually. Despite recent advances in our understanding of the molecular underpinnings of advanced colorectal cancer, chemotherapy remains the mainstay of treatment, with limited efficacy. Mutations activating the WNT-signaling pathway are known to drive the majority of colorectal tumors, but no effective therapeutic strategies targeting this pathway have been developed to date. Analysis of genome-wide genetic loss of function screens in cancer cell lines has revealed that colorectal cancers that depend on beta catenin for survival are also vulnerable to loss of casein kinase 1-alpha (CK1A). Direct therapeutic targeting of CK1A is unproven, however, and it is unknown whether there is a direct functional link to beta catenin signaling in colorectal cancer. This proposal builds on preliminary findings to dissect the mechanism of CK1A dependence in colorectal cancer. We will use complementary genetic and pharmacologic approaches to 1) determine the relationship between loss of casein kinase and beta catenin activity, 2) establish the therapeutic efficacy of targeting CK1A in preclinical models, and 3) elucidate downstream phosphorylation targets of CK1A. Results of these investigations have the potential to establish a new treatment approach for colorectal cancer. Dr. Steven Corsello?s long-term goal is to apply insights from systematic cancer vulnerability screens to advance cancer drug discovery for the treatment of gastrointestinal cancers. Dr. Corsello, based at the Dana-Farber Cancer Institute and the Broad Institute, is mentored by Dr. Todd Golub, a pioneer in cancer genomics, and Dr. William Hahn, a leader in cancer biology and functional genetic screening. An expert career advisory committee consisting of Dr. Nathanael Gray, Dr. Adam Bass, and Dr. Brian Wolpin will provide additional mentorship in drug discovery, disease models, and clinical translation. With input from his mentors, Dr. Corsello has developed a comprehensive five-year training plan incorporating laboratory training, didactic studies, and scientific community engagement.